Flibanserin: pharmacokinetics, pharmacology, clinical applications and side effects

General Description

Flibanserin is a non-hormonal therapy for Hypoactive Sexual Desire Disorder (HSDD) in women. Taken orally as a 100 mg tablet at bedtime, it reaches maximum plasma concentrations within an hour with a half-life of approximately 11 hours. Flibanserin selectively activates 5-HT1A receptors while blocking 5-HT2A receptors, modulating dopamine, norepinephrine, and serotonin levels to enhance sexual desire. Clinical trials showed significant improvements in sexual desire, satisfying sexual events, and distress reduction among pre-menopausal women. Common side effects include dizziness, sleepiness, nausea, fatigue, insomnia, and dry mouth. It may cause low blood pressure and syncope, especially when combined with alcohol or certain medications. Patients are advised to avoid alcohol consumption during treatment.

Figure 1. Tablets of flibanserin

Pharmacokinetics

Flibanserin is available as a 100 mg tablet that is taken orally once daily at bedtime. Maximum plasma concentrations occur 45 to 60 minutes after oral dosing with a half-life (t 1/2) of approximately 11 hours. Steady state is achieved within three days. Food moderately affects the rate and extent of flibanserin absorption. Peak plasma concentrations of flibanserin occur at 1.75 to 4 hours postdosing with food, and the extent of exposure is increased up to 56% after a high-fat, high-caloric meal. Grapefruit juice increases flibanserin exposure approximately 38% and C max by 10%. Cytochrome P450 (CYP) 3A4-mediated biotransformation is responsible for most of flibanserin elimination, with negligible or minimal (<10%) contributions from CYP2C9, CYP2C19 and/or CYP2D6. Thus, moderate or strong CYP3A4 inhibitors are contraindicated. ¹

Pharmacology

Flibanserin is a non-hormonal therapy developed for the treatment of HSDD in women. It functions as a multifunctional serotonin agonist and antagonist, targeting specific receptors in the brain. The exact mechanism of action is not fully understood, but it is believed to involve the modulation of dopamine, norepinephrine, and serotonin levels. Flibanserin selectively activates 5-HT1A receptors while blocking 5-HT2A receptors, leading to a reduction in glutamate transmission and subsequent disinhibition of dopaminergic and adrenergic neurons. This restores the balance of excitatory and inhibitory activity in the brain's reward centers, ultimately enhancing sexual desire. Flibanserin's pharmacological effects differ from other drugs such as SSRIs or buspirone, and it does not directly increase dopamine release in the nucleus accumbens, minimizing the risk of abuse potential. ²

Clinical applications

Flibanserin, a non-hormonal therapy for Hypoactive Sexual Desire Disorder (HSDD) in women, has been studied in pre-menopausal and post-menopausal women. Three clinical trials conducted in North America showed consistent and statistically significant improvements in sexual desire, satisfying sexual events, and reductions in sexually related distress among pre-menopausal women treated with flibanserin 100 mg once daily. The patient global impression of improvement indicated a clinically meaningful benefit, with response rates of 43-51% for sexual desire and 50-60% for decreased distress on flibanserin compared to placebo. Responders experienced significantly greater improvement in desire, distress, and satisfying sexual events compared to the overall patient population. It is important to note that individual responses may vary, and it may take up to 8 weeks for efficacy to manifest. If no improvement is reported after 8 weeks, discontinuation of flibanserin treatment is recommended. Similar efficacy results were observed in post-menopausal women with HSDD, although flibanserin is currently not approved for this population. ³

Side effects

Flibanserin has some potential side effects that should be considered. The most commonly reported side effects include dizziness, somnolence (sleepiness), nausea, fatigue, insomnia, and dry mouth. These side effects were generally mild to moderate in severity and occurred more frequently in the first few weeks of treatment. It is important to note that flibanserin may cause low blood pressure and syncope (fainting) in some individuals, especially when taken with alcohol or certain medications. Other less common side effects include headache, flushing, vomiting, and abdominal pain. Additionally, there have been reports of central nervous system (CNS) depression and driving impairment. Patients should be advised to avoid alcohol consumption while taking flibanserin due to the increased risk of hypotension and syncope. ⁴

Reference

1. Addyi® (flibanserin) tablets, for oral use [prescribing information in US]. Raleigh, NC: Sprout Pharmaceuticals, Inc. 2019.

2. Borsini F, Giraldo E, Monferini E et al. BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol, 1995, 352:276-282.

3. Thorp J, Simon J, Dattani D et al. Treatment of hypoactive sexual desire disorder in premenopausal women: Efficacy of flibanserin in the DAISY study. J Sex Med, 2012, 9:793-804.

4. Clayton AH, Brown L, Kim NN. Evaluation of safety for flibanserin. Expert Opin Drug Saf, 2020, 19(1):1-8.